#1 Regenerative injection therapy (RIT) has been in clinical use for over a century.

A form of regenerative injection therapy was used as a hernia treatment in the early 19th century by Dr. Jaynes in Louisiana (Rice, 1936). In the 1950s, George S. Hackett M.D. developed a form of regenerative injection therapy that he termed “prolotherapy”. He found it very successful for the treatment of ligament laxity leading to other musculoskeletal conditions (Hackett, 2008). His focus was on injuries of the tendon as it inserted into the bone (enthesis) and of ligaments that inserted into the bone (fibro-osseous junction) (Zone 3 in the figure below).

The bone tendon and ligament junction is the most common site of injury due to the significant differences in material characteristics between solid bony tissue and flexible tendon/ligament tissues.

#2 Regenerative injection therapy heals injuries that lead to arthritis later in life.

With advances in technology, there has also been a great deal of research done on joint and cartilage injuries. Regenerative solutions have been used to begin the regeneration of tissues. These solutions include hyperosmolar dextrose or mannitol, platelet-derived growth factors and mesenchymal stem cells (Hauser, 2014; DeChellis, 2011). Once injected, these solutions restart your body’s natural healing cascade which promotes the growth of normal cells and tissues.

Regenerative injection therapy is often done with one or more treatment sessions (Distel, 2011; Rabago, 2010; 2013). The end point of treatment is the elimination of joint instability, progressive joint degeneration and pain. Clinically it has been observed that once joint stability is restored, pain and muscle spasms resolve with a return of normal functional biomechanics.

#3 Identifying the source of pain can speed up treatment.

Fluoroscopic or ultrasound-guidance can be used to identify the precise tissue defect that is the source of the pain. Tissue defects can be found even if x-rays and MRIs are absolutely normal. If accurate anatomic localization is difficult, several sessions are usually needed to identify the precise pain generator.

#4 Regenerative injection therapy can treat many chronic and difficult to treat injuries.

Excessive popping or cracking of the spine or joints (joint instability)

#5 Regenerative injection therapy repairs tissues.

Regenerative injection therapy is the only treatment available for the repair of ligament and tendon injuries (Anitua, 2004;Krampera, 2006; Lam, 2003; Liu, 1983; Reeves, 1995). This reverses the abnormal stress on the joint that can lead to future osteoarthritis and pain.

#6 Regenerative injection therapy is successful even if surgery fails

Regenerative injection therapy can also be used if extensive surgery, such as rotator cuff repair, ACL repair, or joint replacement surgery have not been completely successful.

#7 Regenerative injection therapy can work many years after an injury or accident.

Bracing, physical therapy, kinesio taping, and activity modifications can also be helpful, but they do not heal long damaged tissues. Oral medications and corticosteroid injections inhibit or delay the healing cascade which helps with pain but do not heal the underlying tissue injury.

In sports medicine, physicians focus on cartilage, discs and nerves, but we rarely talk about ligaments which keep your bones together, except when it comes to a knee injury. Once a ligament is injured, the structure it holds together tightly becomes loose. With loosening, abnormal motion develops in the joint resulting in occasional pain and a progression to osteoarthritis many years later. With the huge number of musculoskeletal injuries that are treated yearly in the U.S., we need to think more holistically about joint injuries. Unfortunately, those injuries that physicians do not treat properly, results in another joint replacement or an additional member of the millions of Americans who are permanently disabled. In my practice, I have been able to treat injuries, even many years later, when I include ligaments in the treatment plan.

Ligaments are amazing structures, and if you know a little about them, you will able to keep them healthy and live pain-free.

Musculoskeletal disorders are the most frequent type of chronic pain condition (Murray CJL, 2012; United States Bone and Joint Initiative, 2014), and is a leading cause of disability in the United States affecting almost 160 million people (IOM, 2011). This type of pain develops when local nociceptors detect chemicals released from damaged tissues such as of the joint capsule, tendons, ligaments and fascia. Nociceptors are free nerve endings that originate in the dorsal root ganglia that release a number of substances including calcitonin gene-related peptide (CGRP) and substance P. These substances are known to cause cellular changes in nerves that result in local tissue sensitization as well as modify central pain pathways (Sanchi-Alfonso V 2000; Seybold VS, 2009). There are many pain generators within tissues, but it is thought that most of the pain associated with musculoskeletal injuries originates from the weakness or laxity within the enthesis of tendons and fibro-osseous junction of ligaments.

Ligaments are important because they:

guide forces through adjacent bones or joints

provide joint proprioception

provide mechanical feedback

provide joint stability by limiting excessive joint range of motion

The thick collagen bundles that make up ligaments are generally aligned along the long axis of the ligament, although not as completely as in a tendon. A ligament may appear as a single structure during joint movement, but at a microscopic level, fibers may tighten or loosen depending on their specific position and the overall force that is applied (Frank, 2004).

Unlike tendons that aligned in one direction, ligaments are aligned in a web to keep the joint stable in many different positions.

Each collagen bundle is made up of a collagen matrix with interspersed fibroblasts which are responsible for collagen synthesis and repair (Frank, 2004). Two-thirds of the ligament weight is water which provides its characteristic viscoelastic properties. The remaining 1/3 is a mixture of collagen (85% of which is type I), glycoproteins, elastin and proteoglycans (Frank, 2004).

Components of a ligament

At the molecular level, collagen is synthesized as procollagen molecules that are secreted into the extracellular space, then the helical collagen molecules line up to form fibrils and subsequently collagen fibers that make up the ligament. An enzyme called lysyl oxidase promotes the placement of crosslinks within and between the collagen molecules. This crosslinking creates the tremendous characteristic strength of ligamentous structures (Frank, 2004).

Ligament anchor in the bone

Direct bonding among structurally different materials can be challenging and the body gets around this problem by using a sequential arrangement of tendon or ligament, fibrocartilage, and mineralized fibrocartilage (Sharpey’s fibers) that insert perpendicularly into the bone at the junction. There is significant force that is transmitted through this area so injury and tissue damage most often occur at this junction.

Fibroblasts repair and maintain tissues

Fibroblasts are responsible for matrix synthesis and repair and appear isolated and interspersed throughout the ligament. They are thought to communicate via cytoplasmic extensions that may extend long distances resulting in a complex 3-dimensional structure (Benjamin, 2000; Lo, 2002). Gap junctions have also been detected within the cytoplasmic extensions suggesting a potential to coordinate tissue-wide cellular and metabolic responses (Frank, 2004). This gives fibroblasts the capacity to coordinate regional tissue repair.

2. Ligament biomechanics

Nonlinear behavior

Crimp

The microstructure of ligamentous structures are made up of collagen bundles aligned along the long axis of the ligament with a crimp or “waviness” along its length. Crimp is thought to play a specialized biomechanical role during loading, allowing the collagen fibers to straighten (uncrimp), so the ligament may elongate without tissue damage under a constant or cyclically repetitive load (Amiel, 1995). It results in a nonlinear elasticity, but with continued loading, a nearly linear stiffness develops until complete failure of the tissue.

Viscoelastic behavior

Viscoelasticity refers to the time dependent mechanical relationship between stress and strain that is not constant but dependent on the time of displacement or load. In other words, tissues are stiffer and stronger with high strain than with low strain. There are two major types of viscoelastic behavior, creep and stress relaxation.

Creep

Creep describes increasing deformation under constant load. This contrasts with elastic material which does not deform no matter how long the load is applied. If a ligament is placed under prolonged stress, within its load-bearing capacity (such as in prolonged slouching) then the creep will not immediately return to its pre-load form (loss of energy) because of a concept called hysteresis. Hysteresis describes how once a force is applied that has stretched the tissue and it is then removed, the tissue doesn’t return to its original length. This has to do with energy loss during the stretching process and the process of breaking bonds that had formed between the collagen (hysteresis may be temporary if bonds reconstitute). This process occurs with progressive stretching of tissues.

Stress relaxation

The second form of viscoelastic behavior is stress relaxation. This tissue characteristic describes how stress on a tissue will be reduced or the stress within the ligament will decrease under a constant deformation or strain.

3. Injury and repair of ligaments

Ligament healing occurs in three phases: bleeding/inflammation, cellular and matrix proliferation and remodeling with maturation.

Phase 1: Inflammatory phase

In the first phase, the ligament ends retract with the formation of a blood clot which is replaced with cellular infiltrate, with associated increased vascularity at the site.

Phase 2: Cellular and matrix proliferation

In the second proliferative phase, scar tissue is formed by hypertrophic fibroblastic cells. The scar tissue progresses after a few weeks from an initially disorganized structure to well aligned but smaller collagen fibers made up to more type III and type V collagen.

Phase 3: Tissue remodeling with maturation

The third and final phase of ligament healing is the process of remodeling and maturation. In this phase there is continued work on the altered collagen types, continuing collagen crosslinking, thickening and maturation of the collagen fibrils as well as improved cell connections and innervation. In this phase, the viscoelastic properties can recover to within 10-20% of normal, meaning that the healed ligament is less efficient in maintaining a load.

Ligament scars also demonstrate inferior creep properties. Complete ligament healing continues to be elusive (Frank, 2004), and the final overall strength of a ligament is also affected by its location, degrees of crimp, aging, pregnancy, diabetes, immobilization and use of NSAIDs.

4. Repetitive ligament injuries (micro-trauma)

If the mechanical properties of the ligament are temporarily altered, it cannot sustain reapplied loads in the normal way, so it is prone to injury in a process called fatigue failure. Each subsequent application of force further weakens the tissue although the damage may not be apparent. With further repetitive activities, the weakness will accumulate and the tissue will eventually fail at a much lower load than what would be expected to result in injury. Repetitive physical activity and reloading of the ligament over prolonged periods without sufficient rest and recovery creates cumulative micro-trauma. This results in chronic inflammation that is associated with collagen matrix atrophy and degeneration creating a permanently damaged, weak and non-functional ligament (Leadbetter, 1990).

A silent chronic inflammation that in some cases may have been developing over many years appears one day as a permanent disability associated with pain, limited motion, weakness and other disorders (Safran, 1985).

A common analogy is metal fatigue and subsequent failure that occurs with repetitive bending of, for example, a paper clip. Bending a paper clip once will not result in metal failure, but with repetitive bending, the metal will fatigue and ultimately fail. This is why tissues fatigue and eventually fail without a history of obvious trauma. With a sprain injury or a partial rupture of the ligament, the healing process, may not result in full recovery of the functional properties of the tissue with up to 50-70% of the ligament’s original structural and functional characteristics restored (Andriacchi, 1956; Woo, 1980).

Chronic musculoskeletal pain is due to incomplete repair of fibrous connective tissue which results in ligament and tendon weakness or laxity.

When these damaged tissues are quickly loaded, mechanoreceptors are activated to protect the tissue resulting in pain (Leadbetter, 1994). Incomplete healing is common after a tendon or ligament injury (Browner, 1992). Even submaximal activities that are repetitive may also result in tissue damage, but may not be sufficient to stimulate a healing response so there is an accumulation of tissue overload and damage which is imperceptible until there is enough tissue damage and patients will describe a sudden onset of pain. The use of NSAIDs may also delay or even limit the healing response as well. Electron-microscope images of ligaments reveal that submaximal loading can disrupt some fibers. Some collagen fibers can lose their wavy appearance suggesting the development of a permanent deformation. This suggests that ligaments may continually experience microstructural damage as a result of strenuous activities. This results in overuse injuries as the tissues become further damaged and weakened, resulting in a chronic pain syndrome.

5. Effect of immobilization

With immobilization or reduced physical activity there is decreased overall collagen mass and metabolism, collagen fiber diameter, fibril density and fibril number (Amiel, 1983). Immobilization also results in increased osteoclastic activity with resorption of bone and disruption of the pattern of ligament fibers that insert into the bone (Woo, 1987). Yet with moderate repetitive ligament stimulation coupled more importantly with appropriate rest and recovery allows a tissue to increase its strength and thickness to protect joint stability in persons exposed to increased physical activity (Suominen, 1980). Studies have shown that a greater amount of time is needed to regain original strength than the original immobilization (Noyes FR, 1974). It is thought that regular exercise may retard age-related physiologic decline as much as 50 percent (Menard D, 1989).

6. Muscle spasms from ligament injuries

Muscles can also fatigue, but because of their contractile ability, they rarely fail. Muscle spasms occur when the joint capsule, ligament or intervertebral discs are damaged. Muscle spasms occur to brace and protect the damaged area but can also contribute to the symptoms of local pain and stiffness.

Muscle fatigue, which also results from sustained postures, such a prolonged slouched posture results from muscle overload. They are overloaded while trying to support a less than optimal upright position, the accumulation of metabolites and less than optimal blood flow or ischemia results in the perception of pain. The constant muscle contraction limits the free flow of blood through the muscle stimulating pain fibers. If you move and stretch, blood flow is improved and the muscle pain is reduced. Shortened and tight muscles can also restrict the joints leading to greater problems in the future such as osteoarthritis and injuries that do not heal.

7. Ligamentomuscular protective reflex

Tendons transmit muscle force to bone and dissipate energy where as ligaments augment joint stability and guide the direction and magnitude of joint motion. The free nerve endings present in ligament are thought to act as mechanoreceptors that detect joint position, speed, and movement (Akeson WH, 1984) and they are also thought to transmit nociceptive information as well (Panjabi, 1992). Hence, injury in one segment of the body may refer to distant body parts via the sensory nerve endings within ligaments (Rhalmi, 1993).

A reflex activation of muscles by stimulation of the ACL was first noted in 1987 and a ligamento-muscular protective reflex was then identified in most extremity joints (Solomonow, 1987; Solomonow, 2001). The reflex pathways communicate ligament strain to the central nervous system. If it is abnormal, it will then respond by stimulating specific muscles to contract to prevent further joint displacement or injury resulting in muscle spasms. Research has shown that full stabilization of the joint complex can resolve associated trigger points or muscle spasms (Dagenais, 2007; Jansen, 2008; Jensen, 2008; Rabago, 2013).

In the spine, strain of the passive system of the lumbar spine can excite the mechanoreceptors and lead to a reflexive contraction of the associated multifidus muscles (Solomonow, 2003; Williams, 2000). The primary initiator of a reflexive multifidus muscle contraction is strain of the zygapophyseal (facet) joint capsules during creep as the multifidus has been found to have direct insertions on the facet capsules (Little, 2005). This reflexive multifidus contraction has been observed up to three levels above and below the strained lumbar segment. It is thought to protect the spine by increasing stiffness and decreasing excessive displacement of the spinal segments (Solomonow, 2003). When the passive structures of the lumbar spine are subjected to a steady load, similar to slouching or repeated bending, creep develops in the viscoelastic structures. The laxity induced due by the creep phenomenon leads to desensitization of the mechanoreceptors in the viscoelastic structures of the spine (Sbriccoli, 2004; Solomonow, 1999, 2003). The reduction in the protective reflex of the lumbar extensor muscles has been shown to be directly due to the desensitization of the mechanoreceptors caused by laxity in the viscoelastic tissues and unlikely due to muscle fatigue (Solomonow, 1999). Creep within the ligamentous structures increases the laxity of the spine by a clinically undetectable amount desensitizing the mechanoreceptors and inhibiting their ability to monitor segmental motion (Solomonow, 1999). This hinders the reflexive muscular forces that are essential for segmental and overall spine stabilization (Solomonow, 1999). It is thought that increasing ligament laxity in the spine increases the risk of disc degeneration (Acaroglu, 1995)

The effects of prolong (50-minute) static flexion of the lumbar spine was done in an animal study (Williams, 2000). Multifidus EMG activity was present upon initial stress of the supraspinous ligament, but the EMG activity gradually decreased in the first 3 minutes as relaxation occurred within the viscoelastic structures. Following 10-50 minutes of static physiologic loading, multifidus, spinalis and longissimus EMG activity was demonstrated, which corresponds to muscle spasms (Williams, 2000). This study suggests that accumulated submaximal stress of passive tissues may eventually result in damage with reflexive spasms and pain (Adams, 1996). In vivo studies have demonstrated increased muscle tension with two hours of sitting which increases the overall muscle tension within the lumbar spine in addition to the loss of the reflexive inhibition (Beach, 2005). Spinal ligaments may remain compromised for at least seven hours after unloading (LaBry, 2004). This may be due to micro-trauma and acute inflammation within the viscoelastic tissues, a process which has been documented within the supraspinatus ligament (Solomonow, 2003). Continued buildup of inflammatory mediators within the tissue may cause characteristic pain the following morning after sustained strain.

Injury is not associated with the magnitude of the load but the duration of the load (LaBry, 2004).

8. Incomplete recovery from fatigue

Cyclic loading allows for brief periods of partial recovery between each repetition of flexion hence the need for frequent breaks with prolonged sitting (Little, 2005). Studies have shown a reduced resistance to bending after one hour of submaximal lumbar flexion (Adams, 1996).

In one study using human volunteers, 20 minutes of deep flexion followed by a 25 minute rest period resulted in a 50% recovery, and a 50 minute rest period resulted in a 70% recovery from the resulting creep (McGill, 1992). This suggest that recovery rates are longer than expected, and possibly greater than 2 days (LaBry, 2004). These findings explain why sedentary desk jobs increase the risk of mechanical low back pain.

9. The osteoarthritis degenerative cascade

Osteoarthritis is considered a type of organ failure, where one injury to one component leads to damage of the other components. This collectively results in overall joint failure and the development of clinical manifestations of osteoarthritis (Peterfy, 2004). Alterations within the ligaments and their insertions can affect the adjacent bone and synovial tissues in the development of osteoarthritis (Fleming, 2005; McGonagle, 2010; Wheaton, 2011) at, for example, the knee and spine (see below)

Ligaments of the knee

Inflammatory proteins

The imbalance between the breakdown and repair of joint tissues in osteoarthritis is the result of inflammatory mediators, matrix components and mechanical stressors. Nuclear factor-kappa B and mitogen-activated protein kinase pathways play a predominant role in the expression of metalloproteinases and inflammatory genes and proteins that potential catabolism. (Berenbaum, 2011). The endogenous anabolic factors that stimulate bone and cartilage regeneration and remodeling are insulin-like growth factor one (IGF-1), transforming growth factor (TGF)-b and bone morphogenetic proteins (BMPs). (Fan, 2004; Lajeunesse, 2004)

The arthritic bumps on your fingers

Research conducted in the hand has found the collateral ligaments are the source of inflammatory degeneration and of the periarticular pattern of inflammation noted with osteoarthritis of the hand, with considerable degenerative changes near the ligamentous origins. (McGonagle, 2008; Tan, 2005; Tan, 2006). In early osteoarthritis, inflammatory tissue bulges through the joint capsules at characteristic points of weakness between the collateral ligaments and the extensor tendon. In chronic osteoarthritis, firm nodes form at the same site. The restraining effect of the collateral ligaments and the extensor tendons determine the characteristic clinical feature of generalized nodal osteoarthritis. The collateral ligaments influenced the location of both MRI‐determined bone edema and bone erosion in early osteoarthritis. These changes suggest that the interaction between the ligaments and fibrocartilage lead to the development of osteoarthritis. (Tan, 2006)

10. Medications that interrupt tissue repair

Opioids

Narcotics alter the neurological feedback responses of the body, and may also suppress immune system function (Roy, 1996). Opiates have the same action as cytokines and can modulate the immune response by interacting with central and peripheral nervous system receptors creating neuroinflammation, similar to an endotoxin, in the central nervous system (Wang, 2012). Potential mechanisms of this activity include effects on the hypothalamic-pituitary-adrenal axis and the autonomic nervous system. Opioid receptors have also been identified in peripheral nerves and immune inflammatory cells (Vallejo, 2004). Morphine (a type of opioid) has also been found to prolong recovery from neuropathic pain in animal studies (Grace, 2016).

Anti-inflammatory drugs

Anti-inflammatory drugs are only mildly effective in relieving the symptoms of most ligament, tendon and muscle injuries and are potentially deleterious to soft tissue healing (Mehallo, 2006). They are not recommended for muscle injuries, bone (or stress) fractures, or chronic tendinopathy (Ziltener, 2010). A review noted that there was insufficient evidence of a detrimental effect in soft tissue healing when using NSAIDs at standard doses for ≤2 weeks. A limited number of studies demonstrated the impairment of soft tissue to bone healing (Chen, 2013). NSAIDs work by blocking cyclooxygenase enzymes, which convert arachidonic acid to prostaglandins that are involved in the healing response (Radi, 2005). They have been found to delay but not impair ligament healing (Warden, 2006). NSAID should be more carefully used in ligament injury, joint injury and osteoarthritis (Paoloni, 2009).

Corticosteroids

Corticosteroids are known to have inhibitory effects on glycosaminoglycans, proteins, and collagen synthesis (Hollander, 1974). The anti-inflammatory effect of corticosteroids can result in a decrease load to failure of a partially injured tendon (Kapetanos, 1982). Dexamethasone has been found to decrease cell number and collagen synthesis within tenocyte cultures in a concentration-dependent manner with direct effects on tenocyte proliferation and collagen accumulation (Scutt, 2006).

A recap of the 10 secrets you need to know to keep your ligaments healthy:

Ligaments, not muscles, control how forces go through your joint and keep your joints healthy in many different positions.

Ligaments have immense strength; do not stretch them out too far or for too long.

Ligaments do not always heal.

Repetitive strain injuries develop over many years, then appear one day and for no apparent reason.

United States Bone and Joint Initiative: The Burden of Musculoskeletal Diseases in the United States (BMUS), Third Edition, 2014. Rosemont, IL. Available at http://www.boneandjointburden.org. Accessed on November 20, 2015.